A well characterized family of cytokines is the superfamily of heterodimeric cytokines including IL-12, IL-23, IL-27, CLC-sCNTFR, CLC-CLF-1 and IL-35, all of which bind heterodimeric receptors. Heterodimeric cytokines consist of two different subunits. One of these subunits comprises a four-helix bundle domain. IL-23 consists of the p40 subunit, which is shared with the cytokine IL-12, and the p19 or IL-23 alpha subunit which has a 4-helix bundle structure. IL-23 plays an important role in the inflammatory response against infection. It promotes up-regulation of the matrix metalloprotease MMP9, increases angiogenesis and reduces CD8+ T-cell infiltration. Recently, IL-23 has been implicated in the development of cancerous tumors. In conjunction with IL-6 and TGF-β1, IL-23 stimulates naive CD4+ T cells to differentiate into a novel subset of cells called Th17 cells, which are distinct from the classical Th1 and Th2 cells. Th17 cells produce IL-17, a pro-inflammatory cytokine that enhances T cell priming and stimulates the production of pro-inflammatory molecules such as IL-1, IL-6, TNF-alpha, NOS-2, and chemokines resulting in inflammation.
It has been shown that IL-23 is an important mediator of organ specific autoimmune diseases (Yen et al., 2006). Knockout mice deficient in either p40 or p19, or in either subunit of the IL-23 receptor (IL-23R and IL12R-β1) develop less severe symptoms of multiple sclerosis and inflammatory bowel disease. In addition, it has been demonstrated that anti-IL-23(p19) specific antibodies can inhibit EAE, a preclinical animal model of human MS (Chen et al., 2006).
The therapeutic antibodies Ustekinumab (previously also known under the experimental name ONTO 1275 and now approved for the treatment of plaque psoriasis) and Briakinumab (in phase III clinical trial for the treatment of plaque psoriasis and in phase II trial for MS) are human monoclonal antibodies that neutralize both IL-12 as well as IL-23. There is a concern about adverse effects, more in particular the risk for infections, resulting from the IL23/IL-12 cross-reactivity. While Lima et al. (2009) indicated that no cases of tuberculosis or other opportunistic infections were reported in clinical studies using Ustekinumab, the medication guide for STELARA™ states that ‘Some people have serious infections while taking STELARA™, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses. Some people have to be hospitalized for treatment of their infection’. In addition, the side effects reported for Ustekinumab at the Drug.com web site (Drug Information Online) show up to 5% upper respiratory tract infections.
WO2010/066740 describes Alphabody scaffolds as single-chain triple-stranded alpha-helical coiled coil scaffolds. In addition, WO2012/093172 describes Alphabodies directed against cytokines and growth factors, including IL-23.